title: Two carotenoid oxygenases contribute to mammalian provitamin A metabolism.
abstract: Mammalian genomes encode two provitamin A-converting enzymes as follows: the β-carotene-15,15'-oxygenase (BCO1) and the β-carotene-9',10'-oxygenase (BCO2). Symmetric cleavage by BCO1 yields retinoids (β-15'-apocarotenoids, C20), whereas eccentric cleavage by BCO2 produces long-chain (>C20) apocarotenoids. Here, we used genetic and biochemical approaches to clarify the contribution of these enzymes to provitamin A metabolism. We subjected wild type, Bco1(-/-), Bco2(-/-), and Bco1(-/-)Bco2(-/-) double knock-out mice to a controlled diet providing β-carotene as the sole source for apocarotenoid production. This study revealed that BCO1 is critical for retinoid homeostasis. Genetic disruption of BCO1 resulted in β-carotene accumulation and vitamin A deficiency accompanied by a BCO2-dependent production of minor amounts of β-apo-10'-carotenol (APO10ol). We found that APO10ol can be esterified and transported by the same proteins as vitamin A but with a lower affinity and slower reaction kinetics. In wild type mice, APO10ol was converted to retinoids by BCO1. We also show that a stepwise cleavage by BCO2 and BCO1 with APO10ol as an intermediate could provide a mechanism to tailor asymmetric carotenoids such as β-cryptoxanthin for vitamin A production. In conclusion, our study provides evidence that mammals employ both carotenoid oxygenases to synthesize retinoids from provitamin A carotenoids.
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Jaume
authors.initials: J
authors.lastname: Amengual
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: M Airanthi K
authors.initials: MAK
authors.lastname: Widjaja-Adhi
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Susana
authors.initials: S
authors.lastname: Rodriguez-Santiago
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hessel
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106. Electronic address: johannes.vonlintig@case.edu.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
mesh_terms: D000818:Animals; D002338:Carotenoids / Q000235:genetics / Q000378:metabolism*; D065366:Cryptoxanthins; D049308:Dioxygenases / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D014801:Vitamin A / Q000235:genetics / Q000378:metabolism*; D014802:Vitamin A Deficiency / Q000201:enzymology / Q000235:genetics; D024341:Xanthophylls / Q000235:genetics / Q000378:metabolism; D019207:beta Carotene / Q000235:genetics / Q000378:metabolism; D050559:beta-Carotene 15,15'-Monooxygenase / Q000235:genetics / Q000378:metabolism*
chemical_list: D065366:Cryptoxanthins; D024341:Xanthophylls; C427759:beta-apo-10'-carotenal; D019207:beta Carotene; D014801:Vitamin A; D002338:Carotenoids; D049308:Dioxygenases; C493359:Bco1 protein, mouse; C506534:BCO2 protein, human; C481678:Bco2 protein, mouse; C493358:BCO1 protein, human; D050559:beta-Carotene 15,15'-Monooxygenase
keywords: Carotenoid; Enzymes; Liver; Metabolism; Vitamin A